ESTROGEN INDUCTION OF PITUITARY HYPERPLASIA

一种研究激素依赖性肿瘤生长的新系统 和正常生长一样，是雌激素诱导的脑垂体瘤。 17β-雌二醇延长治疗(1-3个月)或 己烯雌酚诱导垂体肿瘤的作用 (Fischer 344(F344)大鼠的高催乳素瘤)，而SpragueDawley 衍生(SD)菌株对此类肿瘤具有抗药性。我们已经进行了 基因实验表明，肿瘤中的差异 菌株之间的易感性不是由单个基因特性引起的，而是由VaS引起的 可能是因为基因数量很少(2-4个)。短期(2-4天) 雌激素治疗增加SD和F344的DNA合成 脑下垂体。然而，在SD菌株中，DNA合成在5个或5个月后下降 额外6天的雌激素治疗，而DNA合成增加 只要给予雌激素，F344菌株就会持续存在。我们的 工作假说是肿瘤易感性的差异 这些菌株是由于一种复制抑制机制发挥作用 在SD菌株中抑制雌激素刺激的细胞增殖，但 缺乏F344脑下垂体。这项提案的总体目标是 是确定与雌激素诱导相关的特定基因产物(S) 垂体腺的生长及其易感性或抗药性 雌激素诱导的F344和SD大鼠肿瘤形成。 细胞复制和细胞周期调控的关键元件包括 Cyclins，似乎在G1和在G2/M转换中起作用 细胞周期。我们建议研究雌激素对垂体Gl的调节作用 Cyclin基因的表达和确定Cyclin基因的表达是否符合 我们之前提出的解释雌激素的遗传模型-- 诱发F344肿瘤。这些研究可能扩展到已知的抑制子。 基因和其他重要的细胞周期基因。我们还建议使用 消减杂交鉴定菌株特异性基因产物 由于细胞周期蛋白或其他参与生长调节的基因 激素依赖型肿瘤系统。

A novel system in which to study both hormone-dependent tumor growth as well as normal growth is the estrogen induction of pituitary tumors. Prolonged treatment (1-3 months) with 17beta-estradiol (E2) or diethylstilbestrol results in the induction of pituitary tumors (hyperprolactinomas) in Fischer 344 (F344) rats whereas Sprague-Dawley derived (SD) strains are resistant to such tumors. We have conducted genetic experiments indicating that the difference in tumor susceptibility between strains was not due to a single gene trait but vas probably due to a small (2-4) number of genes. Short-term (2-4 days) treatment with estrogen increases DNA synthesis in both SD and F344 pituitaries. However, DNA synthesis declines in the SD strain after 5 or 6 additional days of estrogen treatment, whereas elevated DNA synthesis persists in the F344 strain as long as estrogen is administered. Our working hypothesis is that the difference in tumor susceptibility between the strains is due to a replication repression mechanism that functions in the SD strain to restrain estrogen-stimulated cell proliferation but is deficient in F344 pituitaries. The overall objective of this proposal is to identify specific gene product(s) that relate to estrogen-induced pituitary growth and to either susceptibility or resistance of estrogen-induced tumor formation in F344 and SD rats. Key elements in cell replication and cell cycle regulation include the cyclins, which appear to function in Gl and in the G2/M transition of the cell cycle. We propose to study estrogen regulation of pituitary Gl cyclin gene expression and determine whether cyclin gene expression fits the genetic models we have previously proposed to explain estrogen-- induced F344 tumors. These studies may be extended to known repressor genes and other essential cell cycle genes. We also propose to use subtractive hybridization to identify strain-specific gene products such as the cyclin or other genes involved in growth regulation in this hormone-dependent tumor system.